Neuroscience a Journey Into Understanding , Observation and Application of Metabolic Rate
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Clinical Applications of Neuroscience A Journey into Understanding , Observation and Application of Metabolic Rate Presented by the Carrick Institute for Graduate Studies Frederick Robert Carrick, DC, PhD, DACAN, DABCN, DACNB, DAAPM, FRCPN, FACCN, FAAFN, FEAC (Neurology), FACFN, FABVR, FABES, FABCDD, FICC Professor Emeritus of Neurology, Parker College Distinguished Post Graduate Professor of Clinical Neurology, Logan College Professor of Clinical Neurology, Carrick Institute J. Brandon Brock RN, BSN, MSN, NP-C, DC, DACNB, FACFN, FABVR, FABCDD, FABNN, FABES, FICC, R.NCS.T, CNCT Professor of Neurology, Carrick Institute Family Nurse Practitioner Chiropractic Neurologist / Fellow - Electrodiagnosis, Vestibular Rehabilitation, Nutrition and Neurochemistry, Childhood Disorders. Copyright © 2012 J. Brock / Carrick Institute, All Rights Reserved Special thank you to all of the Carrick Institute Faculty. Each of which have contributed to the growth of this course, the concepts discussed and applications that have been developed. Clinical Features of – Neurological Death • In order to understand neurological conditions from a functional perspective, one must understand the brain and cortex and related functions. You also cannot bypass ablative neurology. – End organ and receptor – Peripheral nervous system – Spinal cord – Brainstem – Cerebellum – Basal Ganglia – Vasculature – Cortex – Physiology – Labs – Imaging Notes Most Important Factors for Treatment • That you know where the problems is from an anatomic point of view. To do this, you have to be able to do a physical examination and patient intake. • The next part of this is to know which receptor based systems will activate the area of pathology. • To be cross trained. Endocrinology, immunology, functional lab analysis, diagnostics and medication. The trick here is learning how to combine metabolic therapy and receptor based therapy in the right order and the right times. (Best therapists the exist at the best at this). • Be the master at controlling fuel for delivery. • Be the master at giving the right combination of treatments at the appropriate rate. Treatment • Is there a good side and a bad side to activation? • Is there an importance to learning how to monitor for fatigue? • “The difference between good and great functional neurologists is knowing when to treat and how much treatment to give and when to stop”. • Sometimes less is more, sometimes less supplementation is better. Sometimes supplementation is all that will work in a given metabolic situation. Sometimes medications are the only option. Sometimes treatment is out of your scope. Notes Things to Monitor • Any objective clinical finding. • Any subjective clinical finding. • Autonomics • Sensory function • Motor function - movement • Cognition • Ocular function • Reflexogenic function Make your list of what you commonly monitor and how you monitor it “Head Trauma” A Model of Metabolic Function • One head injury, one infection, one exposure to various chemicals can lead to immunologically based – inflammatory mediated periods of concussion that may be sustained for long periods and gain physiological efficiency. Head Trauma • Can lead to the following – Chronic encephalopathy – Neurodevelopmental disorders. – Reactive oxygen species – Reactive nitrogen species – Lipid peroxidation products – Prostaglandin production – Dendritic retraction – Myelin damage – Synaptic injury – Microtubular damage – Mitochondrial suppression. – Cell wall damage – DNA damage – Hyperphosphorylation – Microglial priming – BBB degeneration – Insulin dysregulation – Hormonal fluctuation – Autonomic dysregulation Notes Head Trauma • Several loops / scenarios to consider – Immunological – excitotoxic loop. – Excitotoxic – microglial priming loop. – Peripheral immunological macrophagic infiltration loop. – Dual cytokine – glutamate synergism. – TNF alpha , IL1b, Quinolinic - AMPA, NMDA Kianate antagonism. – IDO – INF gamma – Kyurene – QUIN – tryptophan loop. – QUIN – excitotoxic – hyperphosphorylation loops. – Synuclein – amyloid – tau – Oligomer relationships. Notes Immediate Clinical Considerations to Ponder! 1. Is there a component of conservativeTrauma treatment (Trauma –for immune head trauma? – excitotoxic loops) 2. Is there a metabolic link to trauma? 3. Can traumatic situations continue• Excitoto accumulate-toxicity sustained tissue damage? 4. Are there ways to make a change• inReactive this loop? O2 Species 5. Can this loop create collateral damage• Reactive – disease? nitrogen species 6. Is there a methodical way to deal• withAccumulation this story? of Lipid Peroxidation 7. Does this story have anything to• whatProstaglandin we see clinically? activity 8. How does this story related to the• Dendriticmodern day retraction neurological examination? 9. How does this story relate to the• modernSynaptic day injury subjective intake. • Mictrotubular degeneration • Mitochondrial suppression Notes Can you name things • Can you discuss the basic terms and concepts thus far that we are going to expand upon? Receptors and Excito-toxicity Mg2+ NMDA AMPA receptors receptor Ca2+ Na+ synaptic strengthening With lowhigh presynaptic presynaptic activity activity only most some of the of AMPA the AMPA receptors are activated,activated and giving the rise EPSP to ais weak strong. EPSP. The strong EPSP (or back-propagated action potential) liftsUnder the these Mg2+ circumstances block of the NMDA the NMDA receptor. receptor is inactive despite binding of glutamate because its 2+ Thechannel Ca2+ is signal blocked ultimately by Mg leads . to synaptic strengthening. glutamate Ca++ Na+ Mg++ glycine co-agonists open the channel, restingbutLong it -but termis blocked blocked potentiation by Mg++ by Mg++synaptic- not depolarized plasticity NMDA receptors open & unblocked Spectrum of Excitation by Glutamate at NMDA Receptors Energy linked excito-toxicity Autoimmunity to Excito-toxins NMDA receptors Genetic disruption Inflammation BBB dysfunction Glutamate Genetic Excitotoxicity - damage to Excess excitation neurons - psychosis - mania Excitotoxicity - panic - slow neurodegeneration Normal excitation and long-term potentiation Excitotoxicity - catastrophic neurodegeneration NMDA Receptor Summary • What helps control NMDA receptors. – Activation – Genetics – EEE / Mitochondrial function / BBB / Inflammation – Stress (Catecholamine levels). – Immune modulation. – Homocysteine levels – B vitamins – EFA’s – Heavy metal modulation – Mg – Drugs: Memantine, Amantidine, Ketamine, d-cycloserine, L calcium channel blockers. We will discuss how the NMDA pathway ties into glutamate and other transmitters as we progress through the lecture. DISC-1 neuregulin DISC-1 Consider dysfunction Inflammation, Activation, EEE death inadequate neurogenesis poor neuronal migration DISC-1 inadequate neuregulin synapse selection/ axonal neurite outgrowth abnormal glia poorly abnormal innervated development myelination dendritic tree • What therapies or interventions can you use to have a direct impact in the receptor – calcium based systems we just discussed? Link to Calcium and Magnesium Disturbances in Calcium levels • Seen in virtually every disease in the central nervous system that is considered to be related to “neurodegeneration”. Virtually all other mechanisms that occur have this as a cornerstone to its pathophysiological model. • If the homeostatic control mechanism of calcium is disturbed, a disease process will occur. Calcium Control Calcium levels – control and concentrations determine whether a cell will grow or degenerate 1. Action potentiation 2. Calcium receptors activated 1. Voltage gated calcium channels 2. NMDA receptors 3. ACH / glutamate receptors 3. Calcium levels rise via influx into the cytosol 4. Calcium levels rise via influx from the endoplasmic reticulum. 5. This influx must happen to create learning and memory. (ie – hippocampus) 6. LTP is divided into three temporal phases 1. STP (Short term): Activated via protein kinase and protein synthesis independent 2. E-LTP (Early long term potentiation): Activated via protein kinases and the insertion of glutamate receptors into the post synatptic membrane. 3. This will recycle the activation of the AMPAR. Notes AMPAR ACH / Glutamate Threonine / tyrosine A Functional Nervous System Receptor Activation (Trk/P75NTR/RTK/NMDA Receptors) Temporal/Spatial Summation EPSP/IPSP Fuel (O2 & Glucose) Na & Ca K Pathologies Synaptogenesis Mg Receptor health/formation NMDA/AMPA: ATP Plasticity Glutamate receptors Mitochondria Cellular health Kinase activation LTP Apoptosis CIEGR C-fos/jun/mar Kinases: NT Production transfer phosphates from ATP (phosphorylation) Microglial cells and Up-regulates cytokines 2nd order neuron An Excitotoxic Nervous System Receptor Activation Inflammation Temporal/Spatial Summation Excessive Glutamate/Aspartate: EPSP/IPSP brain injury, inflammation, exogenous intake, X mitochondrial damage, etc. Fuel (O2 & Glucose) Na & CaCa K X Synaptogenesis Mg Receptor health/formation Plasticity NMDA/AMPA: ATPX X Glutamate receptors MitochondriaX Activates: Cellular Xhealth Kinase-Proteases activation damage cell proteins -Phospholipases damage lipids LTP -Endonucleases damage DNA X -iNOS & Super Oxide Anion -PerioxynitrateCIEGR C-fos/jun/mar NT Production Up-regulates 2nd order neuron Notes There are many forces at work in in the nervous system: AMPA – Kainate – NMDA – Glutamate – Plastic responses Calcium Induced Excito-toxicity • Apoptotic Pathway – Intracellular calcium dysregulation – Induces DNA degredation